Disease, injury and surgery can result in localized tissue damage and morbidity. For example, the principal treatment for occlusive vascular diseases is angioplasty, a procedure in which a balloon is inserted into the vessel and then inflated to dilate the area of narrowing. During inflation, the balloon can damage the vessel wall. It appears that as a result of this damage, in 30 to 50% of cases, the initial increase in lumen dimensions is followed by a localized re-narrowing (restenosis) of the vessel over a time of three to six months. Thus, restenosis can result in the dangerous and localized renarrowing of a patient's vessel at the site of the recent angioplasty. Like many other localized diseases, restenosis is complex and at present there is no clinically effective treatment for this disease. Gibbons et al., Molecular Therapies for Vascular Diseases, Science vol. 272, pages 617-780 (May 1996).
Restenosis, like many other localized injuries and diseases, has responded poorly to pharmacological therapies and agents. Numerous pharmacological agents have been clinically tested, and none have demonstrated an unequivocal reduction in the incidence of restenosis. However, the failure of these pharmacological therapies may arise from the systemic intolerance of the doses required to achieve local beneficial effects or in the difficulty of providing controlled administration of proper dosages over time. Accordingly, one possible reason for the failure of these therapies is that submaximal doses of pharmacological agents are being administered to avoid the serious side-effects that might result from systemic administration of the proper dosage.
To address this problem, various researchers have proposed methods for site-specific delivery of pharmacologic and molecular therapies. These methods include the direct deposition of therapeutic agents into the arterial wall through an intravascular delivery system, systemic administration of therapeutic agents that have a specific affinity for the injured or diseased tissue, and systemic administration of inactive agents followed by local activation.
Angina pectoris, a symptom of ischemic heart disease, represents one such condition where localized myocardial injury results in pain. Angina pectoris is the occurrence of symptoms characterized as substernal chest pain or pressure with radiation to the left arm, angle of the jaw, shoulder or abdomen. Atypical forms of angina pectoris have also been described. These symptoms are due to myocardial ischemia. If ischemia matures into an infarction, the patient's anginal symptoms commonly escalate as well. Crescendo angina is a marker for progressive myocardial ischemia. Although medical treatment modalities are familiar to practitioners skilled in this art, certain patients are refractory to medical management. In these patients, angina persists despite optimal medical treatment. Although angina pectoris is often a useful symptom for the diagnosis of certain heart conditions, in refractory cases the usefulness of angina pectoris as an indicator of disease is outweighed by the limitation of function it causes for the patient.
Interventions to improve myocardial perfusion act upon the underlying ischemic pathophysiology, but do not provide immediate relief of anginal pain. Thus, despite enhanced vascularity to the myocardium, the patient may still experience angina while the tissues are responding to the revascularization procedure. Operative procedures for specific relief of anginal pain have been employed in cases of refractory angina, albeit with high rates of associated morbidity. These procedures accomplish some form of surgical denervation. Claes et al., Angina pectoris treated by thoracoscopic sympathectomy, Cardiovasc. Surg. 4(6):830, 1996. Localizing the procedure for denervation has the benefit of avoiding the potential electrophysiological consequences of truncal sympathetic ablation procedures. Highly selective localized cardiac denervation has been suggested as the mechanism for the clinical relief of angina following transmyocardial laser treatment. Kwong et aL, Transmyocardial laser treatment denervates canine myocardium, J. Thorac. Cardiovasc. Surg. 114(6):883-9, 1997. All of these procedures result in permanent alterations to the nerve supply of the myocardium, whereas only temporary interventions are necessary for relief of angina if the underlying area of ischemic myocardium has been effectively treated.
At present, systems exist that attempt to achieve localized delivery of therapeutic agents. These systems include dual balloon delivery systems that have proximal and distal balloons that are simultaneously inflated to isolate a treatment space within an arterial lumen. A catheter extends between the two balloons and includes a port that can admit within the treatment space between the balloons an aqueous medium, typically one containing a therapeutic agent. Pressure can be applied to the medium to create conditions conducive to intramural infusion. Other balloon-based localized delivery systems include porous balloon systems, hydrogel-coated balloons and porous balloons that have an interior metallic stent. Other systems include locally placed drug-loaded coated metallic stents and drug-filled polymer stents. Wilensky et al., Methods and Devices for Local Drug Delivery in Coronary and Peripheral Arteries, Trend Cardiovasc Med, vol. 3 (1993).
Although these systems can provide working devices for local drug delivery, the efficacy of these devices turns on, and is limited by, a number of factors including the rate of fluid flux through the vascular wall, the residence time of the deposited agent and the local conditions and vasculature of the deposition site. Essentially, the success of these systems is limited by the amount of time that a delivered drug will stay resident locally before being carried downstream by circulating blood. Further, to the extent that these systems allow the therapeutic agent to be carried away, these systems run the risk of applying a therapeutic agent to areas of the patient's vasculature where such agents may not be beneficial. Additionally, these existing systems are limited by the amount of drug that can be delivered to the diseased site. Moreover, drug filled polymer stents have structural problems that argue against their use. It is understood by those skilled in these arts that regional anesthesia by local infiltration has a success rate proportional to the accurate anatomic installation of the anesthetic solution. Strichartz et al., "Local anesthetics," pp. 437-470 in Anesthesia, Third Ed., R. D. Miller, ed. (New York: Churchill Livingston, 1990).
It would be advantageous to develop other methods of treatment for patients having localized cardiovascular conditions and in particular to develop methods of treatment that reduce adverse side effects and have heightened efficacy.